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Synthesis of micellar-like terpolymer nanoparticles with reductively-cleavable cross-links and evaluation of efficacy in 2D and 3D models of triple negative breast cancer

Monteiro, Patrícia F.; Gulfam, Muhammad; Monteiro, Cíntia J.; Travanut, Alessandra; Abelha, Thais Fedatto; Pearce, Amanda K.; Jerôme, Christine; Grabowska, Anna M.; Clarke, Philip A.; Collins, Hilary M.; Heery, David M.; Gershkovich, Pavel; Alexander, Cameron

Authors

Muhammad Gulfam

Cíntia J. Monteiro

Alessandra Travanut

Thais Fedatto Abelha

Amanda K. Pearce

Christine Jerôme

Anna M. Grabowska

Philip A. Clarke

Hilary M. Collins

David M. Heery

Pavel Gershkovich

Cameron Alexander



Abstract

© 2020 Elsevier B.V. Triple negative or basal-like breast cancer (TNBC) is characterised by aggressive progression, lack of standard therapies and poorer overall survival rates for patients. The bad prognosis, high rate of relapse and resistance against anticancer drugs have been associated with a highly abnormal loss of redox control in TNBC cells. Here, we developed docetaxel (DTX)-loaded micellar-like nanoparticles (MLNPs), designed to address the aberrant TNBC biology through the placement of redox responsive cross-links designed into a terpolymer. The MLNPs were derived from poly(ethyleneglycol)-b-poly(lactide)-co-poly(N3-α-ε-caprolactone) with a disulfide linker pendant from the caprolactone regions in order to cross-link adjacent chains. The terpolymer contained both polylactide and polycaprolactone to provide a balance of accessibility to reductive agents necessary to ensure stability in transit, but rapid micellar breakdown and concomitant drug release, when in breast cancer cells with increased levels of reducing agents. The empty MLNPs did not show any cytotoxicity in vitro in 2D monolayers of MDA-MB-231 (triple negative breast cancer), MCF7 (breast cancer) and MCF10A (normal breast epithelial cell line), whereas DTX-loaded reducible crosslinked MLNPs exhibited higher cytotoxicity against TNBC and breast cancer cells which present high intracellular levels of glutathione. Crosslinked and non-crosslinked MLNPs showed high and concentration-dependent cellular uptake in monolayers and tumour spheroids, including when assessed in co-cultures of TNBC cells and cancer-associated fibroblasts. DTX loaded crosslinked MLNPs showed the highest efficacy against 3D spheroids of TNBC, in addition the MLNPs also induced higher levels of apoptosis, as assessed by annexin V/PI assays and increased caspase 3/7 activity in MDA-MB-231 cells in comparison to cells treated with DTX-loaded un-crosslinked MLNP (used as a control) and free DTX. Taken together these data demonstrate that the terpolymer micellar-like nanoparticles with reducible crosslinks have high efficacy in both 2D and 3D in vitro cancer models by targeting the aberrant biology, i.e. loss of redox control of this type of tumour, thus may be promising and effective carrier systems for future clinical applications in TNBC.

Journal Article Type Article
Publication Date Jul 10, 2020
Journal Journal of Controlled Release
Print ISSN 0168-3659
Electronic ISSN 1873-4995
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 323
Pages 549-564
Series ISSN 0168-3659
APA6 Citation Monteiro, P. F., Gulfam, M., Monteiro, C. J., Travanut, A., Abelha, T. F., Pearce, A. K., …Alexander, C. (2020). Synthesis of micellar-like terpolymer nanoparticles with reductively-cleavable cross-links and evaluation of efficacy in 2D and 3D models of triple negative breast cancer. Journal of Controlled Release, 323, 549-564. https://doi.org/10.1016/j.jconrel.2020.04.049
DOI https://doi.org/10.1016/j.jconrel.2020.04.049
Keywords Pharmaceutical Science
Publisher URL https://www.sciencedirect.com/science/article/abs/pii/S0168365920302637
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